Caffeine is a bitter, white crystalline purine, a methylxanthinealkaloid, and is chemically related to the adenine and guanine bases of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). It is found in the seeds, nuts, or leaves of a number of plants native to Africa, East Asia and South America,[11] and helps to protect them against predator insects and to prevent germination of nearby seeds.[12] The most well-known source of caffeine is the coffee bean, a misnomer for the seed of Coffea plants. Beverages containing caffeine are ingested to relieve or prevent drowsiness and to improve performance. To make these drinks, caffeine is extracted by steeping the plant product in water, a process called infusion. Caffeine-containing drinks, such as coffee, tea, and cola, are very popular; as of 2014, 85% of American adults consumed some form of caffeine daily, consuming 164 mg on average.[13]

Caffeine can have both positive and negative health effects. It can treat and prevent the premature infant breathing disorders bronchopulmonary dysplasia of prematurity and apnea of prematurity. Caffeine citrate is on the WHO Model List of Essential Medicines.[14] It may confer a modest protective effect against some diseases,[15] including Parkinson's disease.[16] Some people experience sleep disruption or anxiety if they consume caffeine, but others show little disturbance. Evidence of a risk during pregnancy is equivocal; some authorities recommend that pregnant women limit consumption to the equivalent of two cups of coffee per day or less.[17][18] Caffeine can produce a mild form of drug dependence – associated with withdrawal symptoms such as sleepiness, headache, and irritability – when an individual stops using caffeine after repeated daily intake.[1][3][5]Tolerance to the autonomic effects of increased blood pressure and heart rate, and increased urine output, develops with chronic use (i.e., these symptoms become less pronounced or do not occur following consistent use).[19]

Caffeine is classified by the US Food and Drug Administration as "generally recognized as safe" (GRAS). Toxic doses, over 10 grams per day for an adult[citation needed], are much higher than the typical dose of under 500 milligrams per day. A cup of coffee contains 80–175 mg of caffeine, depending on what "bean" (seed) is used and how it is prepared (e.g., drip, percolation, or espresso). Thus it requires roughly 50–100 ordinary cups of coffee to reach the toxic dose. However, pure powdered caffeine, which is available as a dietary supplement, can be lethal in tablespoon-sized amounts.

Use

Medical

Bronchopulmonary dysplasia in premature infants for both prevention[20] and treatment.[21] It may improve weight gain during therapy[22] and reduce the incidence of cerebral palsy as well as reduce language and cognitive delay.[23][24] On the other hand, subtle long-term side effects are possible.[25]

Some people use caffeine-containing beverages such as coffee or tea to try to treat their asthma.[31] Evidence to support this practice, however, is poor.[31] A It appears that caffeine improves airway function in people with asthma, increasing forced expiratory volume (FEV1) by 5% to 18%, with this effect lasting for up to four hours.[32]

Enhancing performance

Cognitive

Caffeine is a central nervous system stimulant that reduces fatigue and drowsiness.[10] At normal doses, caffeine has variable effects on learning and memory, but it generally improves reaction time, wakefulness, concentration, and motor coordination.[33][34] The amount of caffeine needed to produce these effects varies from person to person, depending on body size and degree of tolerance.[33] The desired effects arise approximately one hour after consumption, and the desired effects of a moderate dose usually subside after about three or four hours.[7]

Caffeine can delay or prevent sleep and improves task performance during sleep deprivation.[35] Shift workers who use caffeine make fewer mistakes due to drowsiness.[36]

Caffeine improves muscular strength and power,[45] and may enhance muscular endurance.[46] Caffeine also enhances performance on anaerobic tests.[47] Caffeine consumption before constant load exercise is associated with reduced perceived exertion. While this effect is not present during to exhaustion exercise, performance is significantly enhanced. This is congruent with caffeine reducing perceived exertion, because exercise to exhaustion should end at the same point of fatigue.[48] Caffeine also improves power output and reduces time to completion in aerobic time trials.[49]

Specific populations

Adults

For the general population of healthy adults, Health Canada advises a daily intake of no more than 400 mg.[50]

Children

In healthy children, caffeine intake produces effects that are "modest and typically innocuous".[51] There is no evidence that coffee stunts a child's growth.[52] For children age 12 and under, Health Canada recommends a maximum daily caffeine intake of no more than 2.5 milligrams per kilogram of body weight. Based on average body weights of children, this translates to the following age-based intake limits:[50]

Age range

Maximum recommended daily caffeine intake

4–6

45 mg (slightly more than in 12 oz of a typical caffeinated soft drink)

7–9

62.5 mg

10–12

85 mg (about ½ cup of coffee)

Adolescents

Health Canada has not developed advice for adolescents because of insufficient data. However, they suggest that daily caffeine intake for this age group be no more than 2.5 mg/kg body weight. This is because the maximum adult caffeine dose may not be appropriate for light-weight adolescents or for younger adolescents who are still growing. The daily dose of 2.5 mg/kg body weight would not cause adverse health effects in the majority of adolescent caffeine consumers. This is a conservative suggestion since older and heavier weight adolescents may be able to consume adult doses of caffeine without suffering adverse effects.[50]

Pregnancy and breastfeeding

The UK Food Standards Agency has recommended that pregnant women should limit their caffeine intake, out of prudence, to less than 200 mg of caffeine a day – the equivalent of two cups of instant coffee, or one and a half to two cups of fresh coffee.[53] The American Congress of Obstetricians and Gynecologists (ACOG) concluded in 2010 that caffeine consumption is safe up to 200 mg per day in pregnant women.[18] For women who breastfeed, are pregnant, or may become pregnant, Health Canada recommends a maximum daily caffeine intake of no more than 300 mg, or a little over two 8 oz (237 mL) cups of coffee.[50]

There are conflicting reports in the scientific literature about caffeine use during pregnancy.[54] A 2011 review found that caffeine during pregnancy does not appear to increase the risk of congenital malformations, miscarriage or growth retardation even when consumed in moderate to high amounts.[55] Other reviews, however, concluded that there is some evidence that higher caffeine intake by pregnant women may be associated with a higher risk of giving birth to a low birth weight baby,[56] and may be associated with a higher risk of pregnancy loss.[57] A systematic review, analyzing the results of observational studies, suggests that women who consume large amounts of caffeine (greater than 300 mg/day) prior to becoming pregnant may have a higher risk of experiencing pregnancy loss.[58]

Doses of caffeine equivalent to the amount normally found in standard servings of tea, coffee and carbonated soft drinks appear to have no diuretic action.[68] However, acute ingestion of caffeine in large doses (at least 250–300 mg, equivalent to the amount found in 2–3 cups of coffee or 5–8 cups of tea) results in a short-term stimulation of urine output in individuals who have been deprived of caffeine for a period of days or weeks.[68] This increase is due to both a diuresis (increase in water excretion) and a natriuresis (increase in saline excretion); it is mediated via proximal tubular adenosine receptor blockade.[69] The acute increase in urinary output may increase the risk of dehydration. However, chronic users of caffeine develop a tolerance to this effect and experience no increase in urinary output.[70][71]

Psychological

Minor undesired symptoms from caffeine ingestion not sufficiently severe to warrant a psychiatric diagnosis are common and include mild anxiety, jitteriness, insomnia, increased sleep latency, and reduced coordination.[33][72] Caffeine can have negative effects on anxiety disorders.[73] According to a 2011 literature review, caffeine use is positively associated with anxiety and panic disorders.[74] At high doses, typically greater than 300 mg, caffeine can both cause and worsen anxiety.[75] For some people, discontinuing caffeine use can significantly reduce anxiety.[76] In moderate doses, caffeine has been associated with reduced symptoms of depression and lower suicide risk.[77]

Some textbooks state that caffeine is a mild euphoriant,[78][79][80] others state that it is not a euphoriant,[81][82] and one states that it is and is not a euphoriant.[83]

Reinforcement disorders

Addiction

Whether caffeine can result in an addictive disorder depends on how addiction is defined. Compulsive caffeine consumption under any circumstances has not been observed, and caffeine is therefore not generally considered addictive.[85] However, some diagnostic models, such as the ICDM-9 and ICD-10, include a classification of caffeine addiction under a broader diagnostic model.[86] Some state that certain users can become addicted and therefore unable to decrease use even though they know there are negative health effects.[87][88]

Caffeine does not appear to be a reinforcing stimulus, and some degree of aversion may actually occur, with people preferring placebo over caffeine in a study on drug abuse liability published in an NIDA research monograph.[89] Some state that research does not provide support for an underlying biochemical mechanism for caffeine addiction.[1][90][91][92] Other research states it can affect the reward system.[93]

"Caffeine addiction" was added to the ICDM-9 and ICD-10. However, its addition was contested with claims that this diagnostic model of caffeine addiction is not supported by evidence.[1][2][94] The American Psychiatric Association's DSM-5 does not include the diagnosis of a caffeine addiction but proposes criteria for the disorder for more study.[84][95]

Dependence and withdrawal

Withdrawal can cause mild to clinically significant distress or impairment in daily functioning. The frequency at which this occurs is self reported at 11%, but in lab tests only half of the people who report withdrawal actually experience it, casting doubt on many claims of dependence.[96] Mild physical dependence and withdrawal symptoms may occur upon abstinence, with greater than 100 mg caffeine per day, although these symptoms last no longer than a day.[1] some symptoms associated with psychological dependence may also occur during withdrawal.[5] Caffeine dependence can involve withdrawal symptoms such as fatigue, headache, irritability, depressed mood, reduced contentedness, inability to concentrate, sleepiness or drowsiness, stomach pain, and joint pain.[1][5]

The ICD-10 includes a diagnostic model for caffeine dependence, but the DSM-5 does not.[3][94] The APA, which published the DSM-5, acknowledged that there was sufficient evidence in order to create a diagnostic model of caffeine dependence for the DSM-5, but they noted that the clinical significance of this disorder is unclear.[3] The DSM-5 instead lists "caffeine use disorder" in the emerging models section of the manual.[3]

Tolerance to the effects of caffeine occurs for caffeine induced elevations in blood pressure and the subjective feelings of nervousness. Sensitization, the process whereby effects become more prominent with use, occurs for positive effects such as feelings of alertness and well being.[96] Tolerance varies for daily, regular caffeine users and high caffeine users. High doses of caffeine (750 to 1200 mg/day spread throughout the day) have been shown to produce complete tolerance to some, but not all of the effects of caffeine. Doses as low as 100 mg/day, such as a 6 oz cup of coffee or two to three 12 oz servings of caffeinated soft-drink, may continue to cause sleep disruption, among other intolerances. Non-regular caffeine users have the least caffeine tolerance for sleep disruption.[97] Some coffee drinkers develop tolerance to its undesired sleep-disrupting effects, but others apparently do not.[98]

Overdose

Consumption of 1–1.5 grams (0.035–0.053 oz) per day is associated with a condition known as caffeinism.[110] Caffeinism usually combines caffeine dependency with a wide range of unpleasant symptoms including nervousness, irritability, restlessness, insomnia, headaches, and palpitations after caffeine use.[111]

Caffeine overdose can result in a state of central nervous system over-stimulation called caffeine intoxication (DSM-IV 305.90).[112] This syndrome typically occurs only after ingestion of large amounts of caffeine, well over the amounts found in typical caffeinated beverages and caffeine tablets (e.g., more than 400–500 mg at a time). The symptoms of caffeine intoxication are comparable to the symptoms of overdoses of other stimulants: they may include restlessness, fidgeting, anxiety, excitement, insomnia, flushing of the face, increased urination, gastrointestinal disturbance, muscle twitching, a rambling flow of thought and speech, irritability, irregular or rapid heart beat, and psychomotor agitation.[109] In cases of much larger overdoses, mania, depression, lapses in judgment, disorientation, disinhibition, delusions, hallucinations, or psychosis may occur, and rhabdomyolysis (breakdown of skeletal muscle tissue) can be provoked.[113][114]

Massive overdose can result in death.[115][116] The LD50 of caffeine in humans is dependent on individual sensitivity, but is estimated to be 150–200 milligrams per kilogram of body mass (75–100 cups of coffee for a 70 kilogram adult).[117] A number of fatalities have been caused by overdoses of readily available powdered caffeine supplements, for which the estimated lethal amount is less than a tablespoon.[118] The lethal dose is lower in individuals whose ability to metabolize caffeine is impaired due to genetics or chronic liver disease.[119] A death was reported in a man with liver cirrhosis who overdosed on caffeinated mints.[120][121][122]

Interactions

Alcohol

According to DSST, alcohol provides a reduction in performance and caffeine has a significant improvement in performance.[124] When alcohol and caffeine are consumed jointly, the effects produced by caffeine are affected, but the alcohol effects remain the same.[125] For example, when additional caffeine is added, the drug effect produced by alcohol is not reduced.[125] However, the jitteriness and alertness given by caffeine is decreased when additional alcohol is consumed.[125] Alcohol consumption alone reduces both inhibitory and activational aspects of behavioral control. Caffeine antagonizes the activational aspect of behavioral control, but has no effect on the inhibitory behavioral control.[126] The Dietary Guidelines for Americans recommend avoidance of concomitant consumption of alcohol and caffeine, as this may lead to increased alcohol consumption, with a higher risk of alcohol-associated injury.

Tobacco

Birth control

Medications

Caffeine sometimes increases the effectiveness of some medications, such as those for headaches.[129] Caffeine was determined to increase the potency of some over-the-counter analgesic medications by 40%.[130]

In the absence of caffeine and when a person is awake and alert, little adenosine is present in (CNS) neurons. With a continued wakeful state, over time it accumulates in the neuronal synapse, in turn binding to and activating adenosine receptors found on certain CNS neurons; when activated, these receptors produce a cellular response that ultimately increases drowsiness. When caffeine is consumed, it antagonizes adenosine receptors; in other words, caffeine prevents adenosine from activating the receptor by blocking the location on the receptor where adenosine binds to it. As a result, caffeine temporarily prevents or relieves drowsiness, and thus maintains or restores alertness.[6]

Receptor and ion channel targets

Caffeine is an antagonist at all four adenosine receptor subtypes (A1, A2A, A2B, and A3), although with varying potencies.[6][131] The affinity (KD) values of caffeine for the human adenosine receptors are 12 μM at A1, 2.4 μM at A2A, 13 μM at A2B, and 80 μM at A3.[131]Knockout mouse studies have specifically implicated antagonism of the A2A receptor as responsible for the wakefulness-promoting effects of caffeine.[131] Antagonism of adenosine receptors by caffeine stimulates the medullary vagal, vasomotor, and respiratory centers, which increases respiratory rate, reduces heart rate, and constricts blood vessels.[6] Adenosine receptor antagonism also promotes neurotransmitter release (e.g., monoamines and acetylcholine), which endows caffeine with its stimulant effects;[6][132]adenosine acts as an inhibitory neurotransmitter that suppresses activity in the central nervous system. Heart palpitations are caused by blockade of the A1 receptor.[6]

Because caffeine is both water- and lipid-soluble, it readily crosses the blood–brain barrier that separates the bloodstream from the interior of the brain. Once in the brain, the principal mode of action is as a nonselective antagonist of adenosine receptors (in other words, an agent that reduces the effects of adenosine). The caffeine molecule is structurally similar to adenosine, and is capable of binding to adenosine receptors on the surface of cells without activating them, thereby acting as a competitive antagonist.[133]

Effects on striatal dopamine

While caffeine does not directly bind to any dopamine receptors, it influences the binding activity of dopamine at its receptors in the striatum by binding to adenosine receptors that have formed GPCR heteromers with dopamine receptors, specifically the A1–D1 receptor heterodimer (this is a receptor complex with 1 adenosine A1 receptor and 1 dopamine D1 receptor) and the A2A–D2 receptor heterotetramer (this is a receptor complex with 2 adenosine A2A receptors and 2 dopamine D2 receptors).[136][137][138][139] The A2A–D2 receptor heterotetramer has been identified as a primary pharmacological target of caffeine, primarily because it mediates some of its psychostimulant effects and its pharmacodynamic interactions with dopaminergic psychostimulants.[137][138][139]

Caffeine from coffee or other beverages is absorbed by the small intestine within 45 minutes of ingestion and distributed throughout all bodily tissues.[147] Peak blood concentration is reached within 1–2 hours.[148] It is eliminated by first-order kinetics.[149] Caffeine can also be absorbed rectally, evidenced by suppositories of ergotaminetartrate and caffeine (for the relief of migraine)[150] and chlorobutanol and caffeine (for the treatment of hyperemesis).[151] However, rectal absorption is less efficient than oral: the maximum concentration (Cmax) and total amount absorbed (AUC) are both about 30% (i.e., 1/3.5) of the oral amounts.[152]

Caffeine's biological half-life – the time required for the body to eliminate one-half of a dose – varies widely among individuals according to factors such as pregnancy, other drugs, liver enzyme function level (needed for caffeine metabolism) and age. In healthy adults, caffeine's half-life is between 3–7 hours.[6]Smoking decreases the half-life by 30–50%,[98] while oral contraceptives can double it[98] and pregnancy can raise it to as much as 15 hours during the third trimester.[98] In newborns the half-life can be 80 hours or more, dropping very rapidly with age, possibly to less than the adult value by age 6 months.[98] The antidepressant fluvoxamine (Luvox) reduces the clearance of caffeine by more than 90%, and increases its elimination half-life more than tenfold; from 4.9 hours to 56 hours.[153]

1,3,7-Trimethyluric acid is a minor caffeine metabolite.[6] Each of these metabolites is further metabolized and then excreted in the urine. Caffeine can accumulate in individuals with severe liver disease, increasing its half-life.[155]

A 2011 review found that increased caffeine intake was associated with a variation in two genes that increase the rate of caffeine catabolism. Subjects who had this mutation on both chromosomes consumed 40 mg more caffeine per day than others.[156] This is presumably due to the need for a higher intake to achieve a comparable desired effect, not that the gene led to a disposition for greater incentive of habituation.

Chemistry

Pure anhydrous caffeine is a bitter-tasting, white, odorless powder with a melting point of 235–238 °C.[8][9] Caffeine is moderately soluble in water at room temperature (2 g/100 mL), but very soluble in boiling water (66 g/100 mL).[157] It is also moderately soluble in ethanol (1.5 g/100 mL).[157] It is weakly basic (pKa of conjugate acid = ~0.6) requiring strong acid to protonate it.[158] Caffeine does not contain any stereogenic centers[159] and hence is classified as an achiral molecule.[160]

The xanthine core of caffeine contains two fused rings, a pyrimidinedione and imidazole. The pyrimidinedione in turn contains two amide functional groups that exist predominantly in a zwitterionicresonance the location from which the nitrogen atoms are double bonded to their adjacent amide carbons atoms. Hence all six of the atoms within the pyrimidinedione ring system are sp2hybridized and planar. Therefore, the fused 5,6 ring core of caffeine contains a total of ten pi electrons and hence according to Hückel's rule is aromatic.[161]

Decaffeination

Extraction of caffeine from coffee, to produce caffeine and decaffeinated coffee, can be performed using a number of solvents. Benzene, chloroform, trichloroethylene, and dichloromethane have all been used over the years but for reasons of safety, environmental impact, cost, and flavor, they have been superseded by the following main methods:

Water extraction: Coffee beans are soaked in water. The water, which contains many other compounds in addition to caffeine and contributes to the flavor of coffee, is then passed through activated charcoal, which removes the caffeine. The water can then be put back with the beans and evaporated dry, leaving decaffeinated coffee with its original flavor. Coffee manufacturers recover the caffeine and resell it for use in soft drinks and over-the-counter caffeine tablets.[171]

Supercritical carbon dioxide extraction:Supercritical carbon dioxide is an excellent nonpolar solvent for caffeine, and is safer than the organic solvents that are otherwise used. The extraction process is simple: CO2 is forced through the green coffee beans at temperatures above 31.1 °C and pressures above 73 atm. Under these conditions, CO2 is in a "supercritical" state: It has gaslike properties that allow it to penetrate deep into the beans but also liquid-like properties that dissolve 97–99% of the caffeine. The caffeine-laden CO2 is then sprayed with high-pressure water to remove the caffeine. The caffeine can then be isolated by charcoaladsorption (as above) or by distillation, recrystallization, or reverse osmosis.[171]

Extraction by organic solvents: Certain organic solvents such as ethyl acetate present much less health and environmental hazard than chlorinated and aromatic organic solvents used formerly. Another method is to use triglyceride oils obtained from spent coffee grounds.[171]

"Decaffeinated" coffees do in fact contain caffeine in many cases – some commercially available decaffeinated coffee products contain considerable levels. One study found that decaffeinated coffee contained 10 mg of caffeine per cup, compared to approximately 85 mg of caffeine per cup for regular coffee.[172]

Detection in body fluids

Caffeine can be quantified in blood, plasma, or serum to monitor therapy in neonates, confirm a diagnosis of poisoning, or facilitate a medicolegal death investigation. Plasma caffeine levels are usually in the range of 2–10 mg/L in coffee drinkers, 12–36 mg/L in neonates receiving treatment for apnea, and 40–400 mg/L in victims of acute overdosage. Urinary caffeine concentration is frequently measured in competitive sports programs, for which a level in excess of 15 mg/L is usually considered to represent abuse.[173]

Analogs

Some analog substances have been created which mimic caffeine's properties with either function or structure or both. Of the latter group are the xanthinesDMPX[174] and 8-chlorotheophylline, which is an ingredient in dramamine. Members of a class of nitrogen substituted xanthines are often proposed as potential alternatives to caffeine.[175][unreliable source?] Many other xanthine analogues constituting the adenosine receptor antagonist class have also been elucidated.[176]

Precipitation of tannins

Natural occurrence

Roasted coffee beans

Around sixty plant species are known to contain caffeine.[178] Common sources are the "beans" (seeds) of the two cultivated coffee plants, Coffea arabica and Coffea canephora (the quantity varies, but 1.3% is a typical value[179]); in the leaves of the tea plant; and in kola nuts. Other sources include yaupon holly leaves, South American holly yerba mate leaves, seeds from Amazonian maple guarana berries, and Amazonian holly guayusa leaves. Temperate climates around the world have produced unrelated caffeine-containing plants.

Caffeine in plants acts as a natural pesticide: it can paralyze and kill predator insects feeding on the plant.[180] High caffeine levels are found in coffee seedlings when they are developing foliage and lack mechanical protection.[181] In addition, high caffeine levels are found in the surrounding soil of coffee seedlings, which inhibits seed germination of nearby coffee seedlings, thus giving seedlings with the highest caffeine levels fewer competitors for existing resources for survival.[182] Caffeine is stored in tea leaves in two places. Firstly, in the cell vacuoles where it is complexed with polyphenols. This caffeine probably is released into the mouth parts of insects, to discourage herbivory. Secondly, around the vascular bundles, where it probably inhibits pathogenic fungi from entering and colonizing the vascular bundles.[183] Caffeine in nectar may improve the reproductive success of the pollen producing plants by enhancing the reward memory of pollinators such as honey bees.[184]

Beverages

Coffee

The world's primary source of caffeine is the coffee "bean" (the seed of the coffee plant), from which coffee is brewed. Caffeine content in coffee varies widely depending on the type of coffee bean and the method of preparation used;[193] even beans within a given bush can show variations in concentration. In general, one serving of coffee ranges from 80 to 100 milligrams, for a single shot (30 milliliters) of arabica-variety espresso, to approximately 100–125 milligrams for a cup (120 milliliters) of drip coffee.[194][195]Arabica coffee typically contains half the caffeine of the robusta variety.[193]
In general, dark-roast coffee has very slightly less caffeine than lighter roasts because the roasting process reduces caffeine content of the bean by a small amount.[194][195]

Tea

Tea contains more caffeine than coffee by dry weight. A typical serving, however, contains much less, since less of the product is used as compared to an equivalent serving of coffee. Also contributing to caffeine content are growing conditions, processing techniques, and other variables. Thus, teas contain varying amounts of caffeine.[196]

Tea contains small amounts of theobromine and slightly higher levels of theophylline than coffee. Preparation and many other factors have a significant impact on tea, and color is a very poor indicator of caffeine content. Teas like the pale Japanese green tea, gyokuro, for example, contain far more caffeine than much darker teas like lapsang souchong, which has very little.[196]

Soft drinks and energy drinks

Caffeine is also a common ingredient of soft drinks, such as cola, originally prepared from kola nuts. Soft drinks typically contain 0 to 55 milligrams of caffeine per 12 ounce serving.[197] By contrast, energy drinks, such as Red Bull, can start at 80 milligrams of caffeine per serving. The caffeine in these drinks either originates from the ingredients used or is an additive derived from the product of decaffeination or from chemical synthesis. Guarana, a prime ingredient of energy drinks, contains large amounts of caffeine with small amounts of theobromine and theophylline in a naturally occurring slow-releaseexcipient.[198]

Other beverages

Mate is a drink popular in many parts of South America. Its preparation consists of filling a gourd with the leaves of the South American holly yerba mate, pouring hot but not boiling water over the leaves, and drinking with a straw, the bombilla, which acts as a filter so as to draw only the liquid and not the yerba leaves.[citation needed]

Guaraná seeds ("beans") are used in making the commercially sold beverage Guaraná Antarctica, which originated in Brazil and is currently the fifteenth most popular soft drink in the world.[citation needed]

The leaves of Ilex guayusa, the Ecuadorian holly tree, are placed in boiling water to make a guayusa tea, which is both brewed locally and sold commercially throughout the world.[citation needed]

Chocolate

Chocolate derived from cocoa beans contains a small amount of caffeine. The weak stimulant effect of chocolate may be due to a combination of theobromine and theophylline, as well as caffeine.[199] A typical 28-gram serving of a milk chocolate bar has about as much caffeine as a cup of decaffeinated coffee. By weight, dark chocolate has one to two times the amount of caffeine as coffee: 80–160 mg per 100 g. Higher percentages of cocoa such as 90% amount to 200 mg per 100 g approximately and thus, a 100-gram 85% cocoa chocolate bar contains about 195 mg caffeine.[187]

Tablets

No-Doz 100 mg caffeine tablets

Tablets offer several advantages over coffee, tea, and other caffeinated beverages, including convenience, known dosage, and avoidance of concomitant intake of sugar, acids, and fluids. Manufacturers of caffeine tablets claim that using caffeine of pharmaceutical quality improves mental alertness.[citation needed] These tablets are commonly used by students studying for their exams and by people who work or drive for long hours.[200]

Other oral products

One U.S. company is marketing oral dissolvable caffeine strips.[201] Another intake route is SpazzStick, a caffeinated lip balm.[202] Alert Energy Caffeine Gum was introduced in the United States in 2013, but was voluntarily withdrawn after an announcement of an investigation by the FDA of the health effects of added caffeine in foods.[203]

Inhalants

There are several products being marketed that offer inhalers that deliver proprietary blends of supplements, with caffeine being a key ingredient.[204] In 2012, the FDA sent a warning letter to one of the companies marketing these inhalers, expressing concerns for the lack of safety information available about inhaled caffeine.[205]

History

Discovery and spread of use

According to Chinese legend, the Chinese emperorShennong, reputed to have reigned in about 3000 BCE, inadvertently discovered tea when he noted that when certain leaves fell into boiling water, a fragrant and restorative drink resulted.[207] Shennong is also mentioned in Lu Yu's Cha Jing, a famous early work on the subject of tea.[208]

The earliest credible evidence of either coffee drinking or knowledge of the coffee plant appears in the middle of the fifteenth century, in the Sufi monasteries of the Yemenin southern Arabia.[209] From Mocha, coffee spread to Egypt and North Africa, and by the 16th century, it had reached the rest of the Middle East, Persia and Turkey. From the Middle East, coffee drinking spread to Italy, then to the rest of Europe, and coffee plants were transported by the Dutch to the East Indies and to the Americas.[210]

Kola nut use appears to have ancient origins. It is chewed in many West African cultures, in both private and social settings, to restore vitality and ease hunger pangs.

The earliest evidence of cocoa bean use comes from residue found in an ancient Mayan pot dated to 600 BCE. Also, chocolate was consumed in a bitter and spicy drink called xocolatl, often seasoned with vanilla, chile pepper, and achiote. Xocolatl was believed to fight fatigue, a belief probably attributable to the theobromine and caffeine content. Chocolate was an important luxury good throughout pre-ColumbianMesoamerica, and cocoa beans were often used as currency.[citation needed]

Chemical identification, isolation, and synthesis

Pierre Joseph Pelletier

In 1819, the German chemist Friedlieb Ferdinand Runge isolated relatively pure caffeine for the first time; he called it "Kaffebase" (i.e., a base that exists in coffee).[213] According to Runge, he did this at the behest of Johann Wolfgang von Goethe.[214][215] In 1821, caffeine was isolated both by the French chemist Pierre Jean Robiquet and by another pair of French chemists, Pierre-Joseph Pelletier and Joseph Bienaimé Caventou, according to Swedish chemist Jöns Jacob Berzelius in his yearly journal. Furthermore, Berzelius stated that the French chemists had made their discoveries independently of any knowledge of Runge's or each other's work.[216] However, Berzelius later acknowledged Runge's priority in the extraction of caffeine, stating:[217] "However, at this point, it should not remain unmentioned that Runge (in his Phytochemical Discoveries, 1820, pages 146–147) specified the same method and described caffeine under the name Caffeebase a year earlier than Robiquet, to whom the discovery of this substance is usually attributed, having made the first oral announcement about it at a meeting of the Pharmacy Society in Paris."

Pelletier's article on caffeine was the first to use the term in print (in the French form Caféine from the French word for coffee: café).[218] It corroborates Berzelius's account:

Caffeine, noun (feminine). Crystallizable substance discovered in coffee in 1821 by Mr. Robiquet. During the same period – while they were searching for quinine in coffee because coffee is considered by several doctors to be a medicine that reduces fevers and because coffee belongs to the same family as the cinchona [quinine] tree – on their part, Messrs. Pelletier and Caventou obtained caffeine; but because their research had a different goal and because their research had not been finished, they left priority on this subject to Mr. Robiquet. We do not know why Mr. Robiquet has not published the analysis of coffee which he read to the Pharmacy Society. Its publication would have allowed us to make caffeine better known and give us accurate ideas of coffee's composition ...

Robiquet was one of the first to isolate and describe the properties of pure caffeine,[219] whereas Pelletier was the first to perform an elemental analysis.[220]

In 1827, M. Oudry isolated "théine" from tea,[221] but it was later proved by Mulder[222] and by Carl Jobst[223] that theine was actually the same as caffeine.

In 1895, German chemist Hermann Emil Fischer (1852–1919) first synthesized caffeine from its chemical components (i.e. a "total synthesis"), and two years later, he also derived the structural formula of the compound.[224] This was part of the work for which Fischer was awarded the Nobel Prize in 1902.[225]

In 1911, caffeine became the focus of one of the earliest documented health scares, when the US government seized 40 barrels and 20 kegs of Coca-Cola syrup in Chattanooga, Tennessee, alleging the caffeine in its drink was "injurious to health".[233] Although the judge ruled in favor of Coca-Cola, two bills were introduced to the U.S. House of Representatives in 1912 to amend the Pure Food and Drug Act, adding caffeine to the list of "habit-forming" and "deleterious" substances, which must be listed on a product's label.[234]

Society and culture

Regulations

The Food and Drug Administration (FDA) in the United States currently allows only beverages containing less than 0.02% caffeine;[235] but caffeine powder, which is sold as a dietary supplement, is unregulated.[236] It is a regulatory requirement that the label of most prepackaged foods must declare a list of ingredients, including food additives such as caffeine, in descending order of proportion. However, there is no regulatory provision for mandatory quantitative labeling of caffeine, (e.g., milligrams caffeine per stated serving size). There are a number of food ingredients that naturally contain caffeine. These ingredients must appear in food ingredient lists. However, as is the case for "food additive caffeine", there is no requirement to identify the quantitative amount of caffeine in composite foods containing ingredients that are natural sources of caffeine. While coffee or chocolate are broadly recognized as caffeine sources, some ingredients (e.g., guarana, yerba maté) are likely less recognized as caffeine sources. For these natural sources of caffeine, there is no regulatory provision requiring that a food label identify the presence of caffeine nor state the amount of caffeine present in the food.[237]

Consumption

Global consumption of caffeine has been estimated at 120,000 tonnes per year, making it the world's most popular psychoactive substance. This amounts to one serving of a caffeinated beverage for every person every day.[238]

Religions

Some Church of God (Restoration) adherents, and Christian Scientists do not consume caffeine.[citation needed] Until recently, the Seventh-day Adventist Church asked for its members to "abstain from caffeinated drinks", but has removed this from baptismal vows (while still recommending abstention as policy).[239] Some from these religions believe that one is not supposed to consume a non-medical, psychoactive substance, or believe that one is not supposed to consume a substance that is addictive. The Church of Jesus Christ of Latter-day Saints has said the following with regard to caffeinated beverages: " . . . the Church revelation spelling out health practices (Doctrine and Covenants 89) does not mention the use of caffeine. The Church's health guidelines prohibit alcoholic drinks, smoking or chewing of tobacco, and 'hot drinks' – taught by Church leaders to refer specifically to tea and coffee."[240]

Gaudiya Vaishnavas generally also abstain from caffeine, because they believe it clouds the mind and over-stimulates the senses.[241] To be initiated under a guru, one must have had no caffeine, alcohol, nicotine or other drugs, for at least a year.[242]

Caffeinated beverages are widely consumed by Muslims today. In the 16th century, some Muslim authorities made unsuccessful attempts to ban them as forbidden "intoxicating beverages" under Islamic dietary laws.[243][244]

Other organisms

Recently discovered bacteria Pseudomonas putida CBB5 can live on pure caffeine and can cleave caffeine into carbon dioxide and ammonia.[245]

Caffeine is toxic to birds[246] and to dogs and cats,[247] and has a pronounced adverse effect on mollusks, various insects, and spiders.[248] This is at least partly due to a poor ability to metabolize the compound, causing higher levels for a given dose per unit weight.[146] Caffeine has also been found to enhance the reward memory of honey bees.[184]

^ abcKarch SB (2009). Karch's pathology of drug abuse (4th ed.). Boca Raton: CRC Press. pp. 229–230. ISBN978-0-8493-7881-2. The suggestion has also been made that a caffeine dependence syndrome exists ... In one controlled study, dependence was diagnosed in 16 of 99 individuals who were evaluated. The median daily caffeine consumption of this group was only 357 mg per day (Strain et al., 1994).Since this observation was first published, caffeine addiction has been added as an official diagnosis in ICDM 9. This decision is disputed by many and is not supported by any convincing body of experimental evidence. ... All of these observations strongly suggest that caffeine does not act on the dopaminergic structures related to addiction, nor does it improve performance by alleviating any symptoms of withdrawal

^ abcdefAmerican Psychiatric Association (2013). "Substance-Related and Addictive Disorders"(PDF). American Psychiatric Publishing. pp. 1–2. Archived from the original(PDF) on 15 August 2015. Retrieved 10 July 2015. Substance use disorder in DSM-5 combines the DSM-IV categories of substance abuse and substance dependence into a single disorder measured on a continuum from mild to severe. ... Additionally, the diagnosis of dependence caused much confusion. Most people link dependence with "addiction" when in fact dependence can be a normal body response to a substance. ... DSM-5 will not include caffeine use disorder, although research shows that as little as two to three cups of coffee can trigger a withdrawal effect marked by tiredness or sleepiness. There is sufficient evidence to support this as a condition, however it is not yet clear to what extent it is a clinically significant disorder.

^Schmidt B (2005). "Methylxanthine therapy for apnea of prematurity: evaluation of treatment benefits and risks at age 5 years in the international Caffeine for Apnea of Prematurity (CAP) trial". Biology of the Neonate. 88 (3): 208–13. doi:10.1159/000087584. PMID16210843.

^Nehlig A (2010). "Is caffeine a cognitive enhancer?". Journal of Alzheimer's Disease. 20 Suppl 1: S85–94. doi:10.3233/JAD-2010-091315. PMID20182035. Caffeine does not usually affect performance in learning and memory tasks, although caffeine may occasionally have facilitatory or inhibitory effects on memory and learning. Caffeine facilitates learning in tasks in which information is presented passively; in tasks in which material is learned intentionally, caffeine has no effect. Caffeine facilitates performance in tasks involving working memory to a limited extent, but hinders performance in tasks that heavily depend on this, and caffeine appears to improve memory performance under suboptimal alertness. Most studies, however, found improvements in reaction time. The ingestion of caffeine does not seem to affect long-term memory. ... Its indirect action on arousal, mood and concentration contributes in large part to its cognitive enhancing properties.

^ abcdefPesta DH, Angadi SS, Burtscher M, Roberts CK (December 2013). "The effects of caffeine, nicotine, ethanol, and tetrahydrocannabinol on exercise performance". Nutrition & Metabolism. 10 (1): 71. doi:10.1186/1743-7075-10-71. PMC3878772. PMID24330705. Caffeine-induced increases in performance have been observed in aerobic as well as anaerobic sports (for reviews, see [26,30,31]). Trained athletes seem to benefit from a moderate dose of 5 mg/kg [32], however, even lower doses of caffeine (1.0–2.0 mg/kg) may improve performance [33]. Some groups found significantly improved time trial performance [34] or maximal cycling power [35], most likely related to a greater reliance on fat metabolism and decreased neuromuscular fatigue, respectively. Theophylline, a metabolite of caffeine, seems to be even more effective in doing so [36]. The effect of caffeine on fat oxidation, however, may only be significant during lower exercise intensities and may be blocked at higher intensities [37]. ... For both caffeine-naïve as well as caffeine-habituated subjects, moderate to high doses of caffeine are ergogenic during prolonged moderate intensity exercise [61]. ... In summary, caffeine, even at physiological doses (3–6 mg/kg), as well as coffee are proven ergogenic aids and as such – in most exercise situations, especially in endurance-type events – clearly work-enhancing [26]. It most likely has a peripheral effect targeting skeletal muscle metabolism as well as a central effect targeting the brain to enhance performance, especially during endurance events (see Table 1). Also for anaerobic tasks, the effect of caffeine on the CNS might be most relevant. ... Muendel et al. [93] found a 17% improvement in time to exhaustion after nicotine patch application compared to a placebo without affecting cardiovascular and respiratory parameters or substrate metabolism. In this sense, nicotine seems to exert similar effects as caffeine by delaying the development of central fatigue as impaired central drive is an important factor contributing to fatigue during exercise. ... The physiological effects of the above mentioned substances are well established. However, the ergogenic effect of some of the discussed drugs may be questioned and one has to consider the cohort tested for every specific substance. However, only caffeine has enough strength of evidence to be considered an ergogenic aid.

^Castellanos FX, Rapoport JL (2002). "Effects of caffeine on development and behavior in infancy and childhood: A review of the published literature". Food and Chemical Toxicology. 40 (9): 1235–1242. doi:10.1016/S0278-6915(02)00097-2.

^Ebenezer I (2015). Neuropsychopharmacology and Therapeutics. John Wiley & Sons. p. 18. ISBN978-1-118-38578-4. However, in contrast to other psychoactive stimulants, such as amphetamine and cocaine, caffeine and the other methylxanthines do not produce euphoria, stereotyped behaviors or psychotic like symptoms in large doses.

^Fishchman N, Mello N. Testing for Abuse Liability of Drugs in Humans(PDF). 5600 Fishers Lane Rockville, MD 20857: U.S. Department of Health and Human Services Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National Institute on Drug Abuse. p. 179. Archived from the original(PDF) on 22 December 2016.

^Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–43. PMC3898681. PMID24459410. DESPITE THE IMPORTANCE OF NUMEROUS PSYCHOSOCIAL FACTORS, AT ITS CORE, DRUG ADDICTION INVOLVES A BIOLOGICAL PROCESS: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type NAc neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement

^Miller PM (2013). "Chapter III: Types of Addiction". Principles of addiction comprehensive addictive behaviors and disorders (1st ed.). Elsevier Academic Press. p. 784. ISBN978-0-12-398361-9. Retrieved 11 July 2015. Astrid Nehlig and colleagues present evidence that in animals caffeine does not trigger metabolic increases or dopamine release in brain areas involved in reinforcement and reward. A single photon emission computed tomography (SPECT) assessment of brain activation in humans showed that caffeine activates regions involved in the control of vigilance, anxiety, and cardiovascular regulation but did not affect areas involved in reinforcement and reward.

^Nehlig A, Armspach JP, Namer IJ (2010). "SPECT assessment of brain activation induced by caffeine: no effect on areas involved in dependence". Dialogues in Clinical Neuroscience. 12 (2): 255–63. PMC3181952. PMID20623930. Caffeine is not considered addictive, and in animals it does not trigger metabolic increases or dopamine release in brain areas involved in reinforcement and reward. ... these earlier data plus the present data reflect that caffeine at doses representing about two cups of coffee in one sitting does not activate the circuit of dependence and reward and especially not the main target area, the nucleus accumbens. ... Therefore, caffeine appears to be different from drugs of dependence like cocaine, amphetamine, morphine, and nicotine, and does not fulfil the common criteria or the scientific definitions to be considered an addictive substance.42

^ ab"ICD-10 Version:2015". World Health Organization. 2015. Retrieved 10 July 2015. F15 Mental and behavioural disorders due to use of other stimulants, including caffeine ...

.2 Dependence syndromeA cluster of behavioural, cognitive, and physiological phenomena that develop after repeated substance use and that typically include a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal state.The dependence syndrome may be present for a specific psychoactive substance (e.g., tobacco, alcohol, or diazepam), for a class of substances (e.g., opioid drugs), or for a wider range of pharmacologically different psychoactive substances. [Includes:]Chronic alcoholismDipsomaniaDrug addiction

^ abcdFerré S (2008). "An update on the mechanisms of the psychostimulant effects of caffeine". J. Neurochem. 105 (4): 1067–1079. doi:10.1111/j.1471-4159.2007.05196.x. PMID18088379. On the other hand, our 'ventral shell of the nucleus accumbens' very much overlaps with the striatal compartment simply described by De Luca et al. (2007) as 'nucleus accumbens shell,' where both studies show that caffeine does not modify the extracellular levels of dopamine. Therefore, the results of both experimental groups are basically the same and point to differential effects of caffeine in different striatal subcompartments. In fact, analyzing the effects of the intrastriatal perfusion of an A1 receptor antagonist in several other striatal compartments showed striking differences compared with the shell of the nucleus accumbens. Thus, A1 receptor blockade significantly increased the extracellular concentration of dopamine, but not glutamate, in the core of the nucleus accumbens and in the caudate–putamen and the effect was more pronounced in the most medial compartments (Boryczet al. 2007). In summary, a subregional difference in the A1 receptor-mediated control of glutamate and dopamine release exists in the striatum ... A2A receptors play a crucial role in the sleep-promoting effects of adenosine and the arousal-enhancing effects of caffeine (Huang et al. 2007; Ferré et al. 2007a). Those A2A receptors are localized in the ventrolateral pre-optic area of the hypothalamus and their stimulation promotes sleep by inducing GABA release in the histaminergic tuberomammillary nucleus, thereby inhibiting the histaminergic arousal system ... chronic caffeine exposure counteracts both motor activation and dopamine release in the nucleus accumbens induced by caffeine or an A1 receptor antagonist ... An additional factor that might play a significant role in caffeine tolerance is the significant increase in plasma and extracellular concentrations of adenosine with chronic caffeine exposure ... The existence of an A1 receptor-mediated glutamate-independent modulation of dopamine release suggested the presence of functional A1 receptors in striatal dopaminergic terminals. ... In the SSM, adenosine acts pre- and post-synaptically through multiple mechanisms, which depend on heteromerization of A1 and A2A receptors among themselves and with D1 and D2 receptors, respectively. Caffeine produces its motor and reinforcing effects by releasing the pre- and post-synaptic brakes that adenosine imposes on dopaminergic neurotransmission in the SSM. By releasing the pre-synaptic brake, caffeine induces glutamate-dependent and glutamate-independent release of dopamine.

^Fischer began his studies of caffeine in 1881; however, understanding of the molecule's structure long eluded him. In 1895 he synthesized caffeine, but only in 1897 did he finally fully determine its molecular structure.

1.
Melting point
–
The melting point of a solid is the temperature at which it changes state from solid to liquid at atmospheric pressure. At the melting point the solid and liquid phase exist in equilibrium, the melting point of a substance depends on pressure and is usually specified at standard pressure. When considered as the temperature of the change from liquid to solid. Because of the ability of some substances to supercool, the point is not considered as a characteristic property of a substance. For most substances, melting and freezing points are approximately equal, for example, the melting point and freezing point of mercury is 234.32 kelvins. However, certain substances possess differing solid-liquid transition temperatures, for example, agar melts at 85 °C and solidifies from 31 °C to 40 °C, such direction dependence is known as hysteresis. The melting point of ice at 1 atmosphere of pressure is close to 0 °C. In the presence of nucleating substances the freezing point of water is the same as the melting point, the chemical element with the highest melting point is tungsten, at 3687 K, this property makes tungsten excellent for use as filaments in light bulbs. Many laboratory techniques exist for the determination of melting points, a Kofler bench is a metal strip with a temperature gradient. Any substance can be placed on a section of the strip revealing its thermal behaviour at the temperature at that point, differential scanning calorimetry gives information on melting point together with its enthalpy of fusion. A basic melting point apparatus for the analysis of crystalline solids consists of an oil bath with a transparent window, the several grains of a solid are placed in a thin glass tube and partially immersed in the oil bath. The oil bath is heated and with the aid of the melting of the individual crystals at a certain temperature can be observed. In large/small devices, the sample is placed in a heating block, the measurement can also be made continuously with an operating process. For instance, oil refineries measure the point of diesel fuel online, meaning that the sample is taken from the process. This allows for more frequent measurements as the sample does not have to be manually collected, for refractory materials the extremely high melting point may be determined by heating the material in a black body furnace and measuring the black-body temperature with an optical pyrometer. For the highest melting materials, this may require extrapolation by several hundred degrees, the spectral radiance from an incandescent body is known to be a function of its temperature. An optical pyrometer matches the radiance of a body under study to the radiance of a source that has been previously calibrated as a function of temperature, in this way, the measurement of the absolute magnitude of the intensity of radiation is unnecessary. However, known temperatures must be used to determine the calibration of the pyrometer, for temperatures above the calibration range of the source, an extrapolation technique must be employed

2.
Psychoactive drug
–
A psychoactive drug, psychopharmaceutical, or psychotropic is a chemical substance that changes brain function and results in alterations in perception, mood, or consciousness. These substances may be used recreationally, to alter ones consciousness, or, as entheogens, for ritual, spiritual, or shamanic purposes. Some categories of drugs, which have medical therapeutic value, are prescribed by medical doctors. There are also some psychoactive substances used in the detoxification and rehabilitation programs for drug users. Psychoactive substances often bring about changes in consciousness and mood that the user may find rewarding. In addition, sustained use of some substances may produce a physical dependence or psychological dependence syndrome associated with somatic or psychological-emotional withdrawal states respectively, Drug rehabilitation aims to break this cycle of dependency, through a combination of psychotherapy, support groups, maintenance and even other psychoactive substances. However, the reverse is true in some cases, that certain experiences on drugs may be so unfriendly. This is especially true of certain deliriants, powerful dissociatives, and classic psychedelics, in part because of this potential for substance misuse, addiction, or dependence, the ethics of drug use is debated. Restrictions on drug production and sales in an attempt to drug abuse are very common among national and sub-national governments worldwide. Ethical concerns have also raised about over-use of these drugs clinically. Psychoactive drug use can be traced to prehistory, there is archaeological evidence of the use of psychoactive substances dating back at least 10,000 years, and historical evidence of cultural use over the past 5,000 years. The chewing of coca leaves, for example, dates back over 8,000 years ago in Peruvian society, medicinal use is one important facet of psychoactive drug usage. However, some have postulated that the urge to alter ones consciousness is as primary as the drive to satiate thirst, hunger or sexual desire. Supporters of this belief contend that the history of use and even childrens desire for spinning, swinging. It is, however, necessary to precisely what is meant by the use of drugs. We do not mean the purely physical craving, but there are not many drugs which have the power of stilling such craving. This relationship is not limited to humans, a number of animals consume different psychoactive plants, animals, berries and even fermented fruit, becoming intoxicated, such as cats after consuming catnip. Traditional legends of sacred plants often contain references to animals that introduced humankind to their use, animals and psychoactive plants appear to have co-evolved, possibly explaining why these chemicals and their receptors exist within the nervous system

3.
Jmol
–
Jmol is computer software for molecular modelling chemical structures in 3-dimensions. Jmol returns a 3D representation of a molecule that may be used as a teaching tool and it is written in the programming language Java, so it can run on the operating systems Windows, macOS, Linux, and Unix, if Java is installed. It is free and open-source software released under a GNU Lesser General Public License version 2.0, a standalone application and a software development kit exist that can be integrated into other Java applications, such as Bioclipse and Taverna. A popular feature is an applet that can be integrated into web pages to display molecules in a variety of ways, for example, molecules can be displayed as ball-and-stick models, space-filling models, ribbon diagrams, etc. Jmol supports a range of chemical file formats, including Protein Data Bank, Crystallographic Information File, MDL Molfile. There is also a JavaScript-only version, JSmol, that can be used on computers with no Java, the Jmol applet, among other abilities, offers an alternative to the Chime plug-in, which is no longer under active development. While Jmol has many features that Chime lacks, it does not claim to reproduce all Chime functions, most notably, Chime requires plug-in installation and Internet Explorer 6.0 or Firefox 2.0 on Microsoft Windows, or Netscape Communicator 4.8 on Mac OS9. Jmol requires Java installation and operates on a variety of platforms. For example, Jmol is fully functional in Mozilla Firefox, Internet Explorer, Opera, Google Chrome, fast and Scriptable Molecular Graphics in Web Browsers without Java3D

4.
Suppository
–
A suppository is a solid dosage form that is inserted into the rectum, vagina or urethra, where it dissolves or melts and exerts local or systemic effects. Suppositories are used to deliver both systemically and locally acting medications, several different ingredients can be used to form the base of a suppository, cocoa butter or a similar substitute, polyethylene glycol, hydrogels and glycerinated gelatin. The type of material used depends on the type of suppository, the type of drug, in 1991, Abd-El-Maeboud and his colleagues conducted a study on suppository insertion in The Lancet, explaining that the torpedo shape helps the device to travel internally, increasing its efficacy. The findings of this study have been challenged as there is insufficient evidence on which to base clinical practice. Alprostadil pellets are urethral suppositories used for the treatment of erectile dysfunction. They are marketed under the name Muse in the United States and its use has diminished since the development of oral impotence medications. Artesunate suppositories Enema Pessary Doyle, D, per Rectum, A History of Enemata, Journal of the Royal College of Physicians of Edinburgh, Vol.35, No.4, pp. 367–370. How Medical Practice Reflects National Culture, The Sciences, Vol.30, No.4, pp. 38–42

5.
European Chemicals Agency
–
ECHA is the driving force among regulatory authorities in implementing the EUs chemicals legislation. ECHA helps companies to comply with the legislation, advances the safe use of chemicals, provides information on chemicals and it is located in Helsinki, Finland. The Agency, headed by Executive Director Geert Dancet, started working on 1 June 2007, the REACH Regulation requires companies to provide information on the hazards, risks and safe use of chemical substances that they manufacture or import. Companies register this information with ECHA and it is freely available on their website. So far, thousands of the most hazardous and the most commonly used substances have been registered, the information is technical but gives detail on the impact of each chemical on people and the environment. This also gives European consumers the right to ask whether the goods they buy contain dangerous substances. The Classification, Labelling and Packaging Regulation introduces a globally harmonised system for classifying and labelling chemicals into the EU. This worldwide system makes it easier for workers and consumers to know the effects of chemicals, companies need to notify ECHA of the classification and labelling of their chemicals. So far, ECHA has received over 5 million notifications for more than 100000 substances, the information is freely available on their website. Consumers can check chemicals in the products they use, Biocidal products include, for example, insect repellents and disinfectants used in hospitals. The Biocidal Products Regulation ensures that there is information about these products so that consumers can use them safely. ECHA is responsible for implementing the regulation, the law on Prior Informed Consent sets guidelines for the export and import of hazardous chemicals. Through this mechanism, countries due to hazardous chemicals are informed in advance and have the possibility of rejecting their import. Substances that may have effects on human health and the environment are identified as Substances of Very High Concern 1. These are mainly substances which cause cancer, mutation or are toxic to reproduction as well as substances which persist in the body or the environment, other substances considered as SVHCs include, for example, endocrine disrupting chemicals. Companies manufacturing or importing articles containing these substances in a concentration above 0 and they are required to inform users about the presence of the substance and therefore how to use it safely. Consumers have the right to ask the retailer whether these substances are present in the products they buy, once a substance has been officially identified in the EU as being of very high concern, it will be added to a list. This list is available on ECHA’s website and shows consumers and industry which chemicals are identified as SVHCs, Substances placed on the Candidate List can then move to another list

6.
Pharmacokinetics
–
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered to a living organism. The substances of interest include any chemical xenobiotic such as, pharmaceutical drugs, pesticides, food additives, cosmetic ingredients, etc. It attempts to analyze chemical metabolism and to discover the fate of a chemical from the moment that it is administered up to the point at which it is eliminated from the body. Pharmacokinetics is the study of how an organism affects a drug, both together influence dosing, benefit, and adverse effects, as seen in PK/PD models. Pharmacokinetic properties of chemicals are affected by the route of administration and these may affect the absorption rate. Models have been developed to simplify conceptualization of the processes that take place in the interaction between an organism and a chemical substance. The various compartments that the model is divided into are commonly referred to as the ADME scheme, absorption - the process of a substance entering the blood circulation. Distribution - the dispersion or dissemination of substances throughout the fluids, metabolism – the recognition by the organism that a foreign substance is present and the irreversible transformation of parent compounds into daughter metabolites. Excretion - the removal of the substances from the body, in rare cases, some drugs irreversibly accumulate in body tissue. The two phases of metabolism and excretion can also be grouped together under the title elimination, the study of these distinct phases involves the use and manipulation of basic concepts in order to understand the process dynamics. All these concepts can be represented through mathematical formulas that have a graphical representation. The model outputs for a drug can be used in industry or in the application of pharmacokinetic concepts. Clinical pharmacokinetics provides many performance guidelines for effective and efficient use of drugs for human-health professionals, in practice, it is generally considered that steady state is reached when a time of 4 to 5 times the half-life for a drug after regular dosing is started. Noncompartmental methods estimate the exposure to a drug by estimating the area under the curve of a concentration-time graph, compartmental methods estimate the concentration-time graph using kinetic models. Noncompartmental methods are more versatile in that they do not assume any specific compartmental model. The final outcome of the transformations that a drug undergoes in an organism, a number of functional models have been developed in order to simplify the study of pharmacokinetics. These models are based on a consideration of an organism as a number of related compartments, the simplest idea is to think of an organism as only one homogenous compartment. However, these models do not always reflect the real situation within an organism

7.
Theobromine
–
Theobromine, formerly known as xantheose, is a bitter alkaloid of the cacao plant, with the chemical formula C7H8N4O2. It is found in chocolate, as well as in a number of foods, including the leaves of the tea plant. It is classified as an alkaloid, which also include the similar compounds theophylline and caffeine. The compounds differ in that caffeine has a methyl group. Theobromine is a slightly water-soluble, crystalline, bitter powder, theobromine is white or colourless, but commercial samples can be yellowish. It has a similar to, but lesser than, that of caffeine in the human nervous system. Theobromine is an isomer of theophylline, as well as paraxanthine, theobromine is categorized as a dimethyl xanthine. Theobromine was first discovered in 1841 in cacao beans by Russian chemist Alexander Voskresensky, synthesis of theobromine from xanthine was first reported in 1882 by Hermann Emil Fischer. Theobromine is the primary found in cocoa and chocolate. Cocoa powder can vary in the amount of theobromine, from 2% theobromine, there are usually higher concentrations in dark than in milk chocolate. Theobromine can also be found in small amounts in the nut, the guarana berry, yerba mate. 28 grams of milk chocolate contains approximately 60 milligrams of theobromine, cocoa beans naturally contain approximately 1% theobromine. Cleavage of the ribose and N-methylation yields 7-methylxanthosine, 7-Methylxanthosine in turn is the precursor to theobromine, which in turn is the precursor to caffeine. Theobromine is a vasodilator, a diuretic, and heart stimulant and it is not currently used as a medicinal drug. Because of this effect, and its ability to dilate blood vessels. In the human body, theobromine levels are halved between 6–10 hours after consumption, theobromine has also been used in birth defect experiments involving mice and rabbits. A decreased fetal weight was noted in rabbits following forced feeding, birth defects were not seen in rats. Possible future uses of theobromine in such fields as cancer prevention have been patented, theobromine has also been shown to improve the microhardness of tooth enamel which could potentiality increase resistance to tooth decay

8.
Density
–
The density, or more precisely, the volumetric mass density, of a substance is its mass per unit volume. The symbol most often used for density is ρ, although the Latin letter D can also be used. Mathematically, density is defined as mass divided by volume, ρ = m V, where ρ is the density, m is the mass, and V is the volume. In some cases, density is defined as its weight per unit volume. For a pure substance the density has the numerical value as its mass concentration. Different materials usually have different densities, and density may be relevant to buoyancy, purity, osmium and iridium are the densest known elements at standard conditions for temperature and pressure but certain chemical compounds may be denser. Thus a relative density less than one means that the floats in water. The density of a material varies with temperature and pressure and this variation is typically small for solids and liquids but much greater for gases. Increasing the pressure on an object decreases the volume of the object, increasing the temperature of a substance decreases its density by increasing its volume. In most materials, heating the bottom of a results in convection of the heat from the bottom to the top. This causes it to rise relative to more dense unheated material, the reciprocal of the density of a substance is occasionally called its specific volume, a term sometimes used in thermodynamics. Density is a property in that increasing the amount of a substance does not increase its density. Archimedes knew that the irregularly shaped wreath could be crushed into a cube whose volume could be calculated easily and compared with the mass, upon this discovery, he leapt from his bath and ran naked through the streets shouting, Eureka. As a result, the term eureka entered common parlance and is used today to indicate a moment of enlightenment, the story first appeared in written form in Vitruvius books of architecture, two centuries after it supposedly took place. Some scholars have doubted the accuracy of this tale, saying among other things that the method would have required precise measurements that would have been difficult to make at the time, from the equation for density, mass density has units of mass divided by volume. As there are units of mass and volume covering many different magnitudes there are a large number of units for mass density in use. The SI unit of kilogram per metre and the cgs unit of gram per cubic centimetre are probably the most commonly used units for density.1,000 kg/m3 equals 1 g/cm3. In industry, other larger or smaller units of mass and or volume are often more practical, see below for a list of some of the most common units of density

9.
Excretion
–
Excretion is the process by which metabolic wastes and other non-useful materials are eliminated from an organism. In vertebrates this is carried out by the lungs, kidneys. This is in contrast with secretion, where the substance may have specific tasks after leaving the cell, excretion is an essential process in all forms of life. For example, in urine is expelled through the urethra. In unicellular organisms, waste products are discharged directly through the surface of the cell, green plants produce carbon dioxide and water as respiratory products. In green plants, the carbon dioxide released during respiration gets utilized during photosynthesis, oxygen is a by product generated during photosynthesis, and exits through stomata, root cell walls, and other routes. Plants can get rid of water by transpiration and guttation. These latter processes do not need added energy, they act passively, however, during the pre-abscission phase, the metabolic levels of a leaf are high. Plants also excrete some waste substances into the soil around them, in animals, the main excretory products are carbon dioxide, ammonia, urea, uric acid, guanine and creatine. The liver and kidneys clear many substances from the blood, aquatic animals usually excrete ammonia directly into the external environment, as this compound has high solubility and there is ample water available for dilution. In terrestrial animals ammonia-like compounds are converted into other materials as there is less water in the environment. Birds excrete their nitrogenous wastes as uric acid in the form of a paste and this is metabolically more expensive, but allows more efficient water retention and it can be stored more easily in the egg. Many avian species, especially seabirds, can also excrete salt via specialized nasal salt glands, in insects, a system involving Malpighian tubules is utilized to excrete metabolic waste. Metabolic waste diffuses or is actively transported into the tubule, which transports the wastes to the intestines, the metabolic waste is then released from the body along with fecal matter. The excreted material may be called dejecta or ejecta, in pathology the word ejecta is more commonly used. UAlberta. ca, Animation of excretion Brian J Ford on leaf fall in Nature

10.
Regulation of therapeutic goods
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The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the level by a single agency. In other jurisdictions they are regulated at the level, or at both state and national levels by various bodies, as is the case in Australia. The role of therapeutic goods regulation is designed mainly to protect the health, regulation is aimed at ensuring the safety, quality, and efficacy of the therapeutic goods which are covered under the scope of the regulation. In most jurisdictions, therapeutic goods must be registered before they are allowed to be marketed, there is usually some degree of restriction of the availability of certain therapeutic goods depending on their risk to consumers. Therapeutic goods in Australia are regulated by the Therapeutic Goods Administration, there are 5 main categories, Normal Medicines - Cough, cold and fever medicines, antiseptics, vitamins and others. Sold freely in pharmacies and some large supermarkets, red Stripe Medicines - These medicines are sold only with medical prescription. Antibiotics, Anti allergenics, Anti inflammatories, and other medicines, in Brazil, governmental control is loose on this type, it is not uncommon to buy this type of prescription medicine over the counter without a prescription. Red Stripe Psychoactive Medicines - These medicines are only with a Special Control white medical prescription with carbon copy. The original must be retained by the pharmacist after the sale, Drugs include anti-depressants, anti-convulsants, some sleep aids, anti-psychotics and other non-habit-inducing controlled medicines. Though some consider them habit inducing, anabolic steroids are also regulated under this category, black Stripe Medicines - These medicines are sold only with the Blue B Form medical prescription, which is valid for 30 days and must be retained by the pharmacist after the sale. Includes sedatives, some anorexic inducers and other habit-inducing controlled medicines, includes amphetamines and other stimulants, opioids and other strong habit-forming controlled medicines. In Canada, regulation of goods are governed by the Food and Drug Act. In addition, the Controlled Drugs and Substances Act requires additional regulatory requirements for controlled drugs, the regulation of drugs in Burma is governed by the Food and Drug Administration and Food and Drug Board of Authority. The regulation of drugs in China is governed by the China Food, Medicines for Human Use in the United Kingdom are regulated by the Medicines and Healthcare products Regulatory Agency. The availability of drugs is regulated by classification by the MHRA as part of marketing authorisation of a product, Medicines in the Republic of Ireland are regulated according to the Misuse of Drugs Regulations 1988. Controlled drugs are divided into five categories based on their potential for misuse, cD1, cannabis, lysergamide, coca leaf, etc. Use prohibited except in limited circumstances where a license has been granted, CD2, amphetamine, methadone, morphine, fentanyl, oxycodone, tapentadol, etc

Graph that demonstrates the Michaelis–Menten kinetics model for the relationship between an enzyme and a substrate: one of the parameters studies in pharmacokinetics, where the substrate is a pharmaceutical drug.

Different forms of tablets, which will have different pharmacokinetic behaviours after their administration.

The time course of drug plasma concentrations over 96 hours following oral administrations every 24 hours. Note that the AUC in steady state equals AUC∞ after the first dose.